BACKGROUND: Dual respiratory viral infections are frequently associated with lower respiratory tract illness in infants. This study aimed to determine the impact of a dual respiratory viral infection on specific aspects of the infant\'s immune response and the clinical course of illness. METHODS: A prospective study was performed with 772 infants hospitalized from October 2000 through July 2004. Sensitive polymerase chain reaction methodology revealed the presence of a single respiratory virus in 443 (57%) of 772 cases, whereas dual infections were identified in 153 (20%) of cases. From 250 infants with confirmed respiratory viral infection, fresh heparinized blood was analyzed for interferon-gamma (IFN-gamma) responses by flow cytometry. Of these, 191 patients had a single infection with respiratory syncytial virus (RSV), rhinoviruses, adenoviruses or influenza viruses; and 59 patients had a dual infection with RSV and rhinoviruses, RSV and adenoviruses, influenza viruses and rhinoviruses or adenoviruses and rhinoviruses. The clinical features and peripheral lymphocyte IFN-gamma responses were compared among infants with single or dual infections. RESULTS: It was found that dual infections with non-RSV respiratory viruses induced peripheral blood mononuclear cell IFN-gamma responses that mimic those of single infections, whereas coinfection with RSV was associated with reduced IFN-gamma responses and a more severe clinical course of lower respiratory tract disease. CONCLUSIONS: The results indicate that the clinical characteristics and the IFN-gamma response differ significantly in single and dual respiratory viral infection, depending on the nature of the simultaneously detected viruses. In dual infections, RSV involvement was associated with a decreased IFN-gamma response in peripheral blood mononuclear cell and an increase in severity of illness.